ACS Medicinal Chemistry Letters最新文献_第6页

Design, Synthesis, and Biological Evaluation of Novel Hydroxyamidine Derivatives as Indoleamine 2,3-Dioxygenase 1 Inhibitors. 吲哚胺2,3-双加氧酶1抑制剂的设计、合成及生物学评价

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-30 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00279

Xiaodan Qiu, Yitong Liu, Xia Zhou, Cong Zhao, Qingguo Meng, Wuli Zhao, Guangzhi Shan

{"title":"Design, Synthesis, and Biological Evaluation of Novel Hydroxyamidine Derivatives as Indoleamine 2,3-Dioxygenase 1 Inhibitors.","authors":"Xiaodan Qiu, Yitong Liu, Xia Zhou, Cong Zhao, Qingguo Meng, Wuli Zhao, Guangzhi Shan","doi":"10.1021/acsmedchemlett.5c00279","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00279","url":null,"abstract":"Indoleamine 2,3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that catalyzes the conversion of tryptophan into kynurenine and represents a potential target for tumor immunotherapy. In this study, we designed and synthesized a series of N'-hydroxyamidine analogues through pharmacophore fusion and bioisosterism principles. The results indicated that compounds I-1 and I-2 exhibited activity similar to that of Epacadostat in inhibiting recombinant hIDO1 and hIDO1 expression in HeLa cells. Moreover, the compounds not only effectively stimulated T cell proliferation but also inhibited the proliferation of Lewis Lung Carcinoma cells. RNA sequencing analysis indicated that these compounds primarily exert immunotherapeutic effects. Surface plasmon resonance and molecular docking confirmed the interactions between the compounds and IDO1. The physicochemical properties along with pharmacokinetic profiles of both compounds were also predicted, and they were found to possess favorable characteristics. The active compounds developed in this research may serve as valuable references for discovering highly effective IDO1 inhibitors.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1401-1409"},"PeriodicalIF":3.5,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Scaffold Hopping Strategy toward New 4‑Aminoquinazolines Active Against Extracellular and Intracellular. 抗细胞外和细胞内活性新4 -氨基喹唑啉的支架跳跃策略。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-30 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00276

Guilherme Arraché Gonçalves, Alexia de Matos Czeczot, Marcia Alberton Perelló, Eric Greve, Renee Allen, Camili Zanella Zotti, Laura Calle González, Andresa Berger, Josiane Delgado Paz, Lídia Klatt Oliveira, Sidnei Moura E Silva, Cristiano Valim Bizarro, Luiz Augusto Basso, Tanya Parish, Pablo Machado

{"title":"Scaffold Hopping Strategy toward New 4‑Aminoquinazolines Active Against Extracellular and Intracellular.","authors":"Guilherme Arraché Gonçalves, Alexia de Matos Czeczot, Marcia Alberton Perelló, Eric Greve, Renee Allen, Camili Zanella Zotti, Laura Calle González, Andresa Berger, Josiane Delgado Paz, Lídia Klatt Oliveira, Sidnei Moura E Silva, Cristiano Valim Bizarro, Luiz Augusto Basso, Tanya Parish, Pablo Machado","doi":"10.1021/acsmedchemlett.5c00276","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00276","url":null,"abstract":"A series of 4-aminoquinazolines was designed through a scaffold hopping approach inspired by pharmacophoric features of known antimycobacterial agents. The compounds were synthesized via a one-pot silylation-amination reaction under solvent-free conditions, affording the desired molecules in 70%-99% yields. Antimycobacterial evaluation using multiple strains and assay platforms revealed potent activity, with MIC values as low as 0.28 μM. Structure-activity relationship analysis identified the N-(3-phenylpropyl)-quinazolin-4-amine scaffold as a promising chemotype. Mechanistic studies indicated that the compounds do not act via QcrB inhibition, membrane disruption, ROS induction, or MmpL3 targeting. The most active derivatives displayed favorable selectivity indices, lacked broad-spectrum antibacterial activity, and demonstrated intracellular efficacy in a macrophage infection model. Despite low metabolic stability, the scaffold's potency, selectivity, and intracellular activity support its potential as a lead series. These findings suggest a novel, yet unidentified mechanism of action and provide a promising starting point for anti-TB drug campaigns.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1410-1419"},"PeriodicalIF":3.5,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel Tricyclic Psychedelic Psychoplastogens as 5‑HT2C Agonists for Treating Neurological Diseases. 新型三环致幻剂作为5‑HT2C激动剂治疗神经系统疾病。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-29 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00381

Ram W Sabnis

引用次数: 0

Discovery of Novel MTA-Cooperative PRMT5 Inhibitors with a 2,3-Dihydro‑1H‑imidazo[1,2‑b]pyrazole Scaffold. 具有2,3-二氢- 1H -咪唑[1,2 - b]吡唑支架的新型mta协同PRMT5抑制剂的发现。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-27 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00185

Yuxin Yang, Zonglong Chen, Yujie Wang, Xun Huang, Chun Hu, Hong Yang, Yingxia Li

引用次数: 0

Development and Preclinical Evaluation of PET Radiotracers Targeting Adenosine A₁ Receptors. 靶向腺苷A1受体的PET示踪剂的开发和临床前评价。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-26 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00249

Abolghasem Gus Bakhoda, Torben D Pearson, Zhan-Guo Gao, Kelly A O'Conor, Seth M Eisenberg, Andrew C Kelleher, Yeona Kang, Jeih-San Liow, Jun Yong Choi, Woochan Kim, Jinpyo Seo, Michael L Freaney, Kenneth A Jacobson, Nora D Volkow, Sung Won Kim

{"title":"Development and Preclinical Evaluation of PET Radiotracers Targeting Adenosine A1 Receptors.","authors":"Abolghasem Gus Bakhoda, Torben D Pearson, Zhan-Guo Gao, Kelly A O'Conor, Seth M Eisenberg, Andrew C Kelleher, Yeona Kang, Jeih-San Liow, Jun Yong Choi, Woochan Kim, Jinpyo Seo, Michael L Freaney, Kenneth A Jacobson, Nora D Volkow, Sung Won Kim","doi":"10.1021/acsmedchemlett.5c00249","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00249","url":null,"abstract":"Several adenosine A1 receptor (A1R) radiotracers for positron emission tomography (PET) have been developed to study their neuromodulatory functions and role in brain disorders. While two xanthine-based radiotracers ([11C]-MPDX and [18F]-CPFPX) have been used in humans, we aimed to improve the metabolic stability and specific binding. Guided by structure-activity relationship (SAR) studies, 10 derivatives were synthesized with binding affinities up to 0.12 nM. Three subnanomolar candidates (3, 8, 9) were radiolabeled with C-11 (t 1/2 = 20.4 min) for evaluation using in vivo PET imaging and ex vivo rodent brain biodistribution. Although [11C]8 demonstrated a higher blood-brain barrier (BBB) permeability, negligible in vivo specific binding was observed. Ex vivo studies indicated that all three compounds are substrates for brain efflux pumps. Despite optimized affinity, BBB permeability and in vivo binding specificity remain challenges. These findings inform development of nonxanthine A1R radiotracers and highly potent CNS A1R drugs.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1365-1372"},"PeriodicalIF":3.5,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Selective Modulation of the GluN2B/C/D Containing N‑Methyl‑d‑Aspartate Receptors: A New Frontier in Targeted Neurotherapeutics. 含N -甲基- D -天冬氨酸受体GluN2B/C/D的选择性调节：靶向神经治疗的新前沿。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-26 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00365

Yinlong Li, Steven H Liang

引用次数: 0

Discovery of Novel c‑MET Inhibitors for Hepatocellular Carcinoma Using an Integrated Virtual Screening Approach. 使用集成虚拟筛选方法发现新的肝细胞癌c - MET抑制剂。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-26 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00173

Rushan Fei, Na Lin, Xin Zhang, Lei Xu, Qingnan Zhang, Zhichao Pan, Xiaowu Dong, Weilin Wang

{"title":"Discovery of Novel c‑MET Inhibitors for Hepatocellular Carcinoma Using an Integrated Virtual Screening Approach.","authors":"Rushan Fei, Na Lin, Xin Zhang, Lei Xu, Qingnan Zhang, Zhichao Pan, Xiaowu Dong, Weilin Wang","doi":"10.1021/acsmedchemlett.5c00173","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00173","url":null,"abstract":"Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide, with the efficacy of current targeted therapies limited by drug resistance and adverse effects. The receptor tyrosine kinase c-MET has been identified as a promising target for HCC therapy due to its involvement in tumor progression, metastasis, and poor prognosis. However, no c-MET inhibitors have been approved for HCC treatment. This study integrates a multistep virtual screening workflow, incorporating molecular docking, machine learning-based predictions, and molecular dynamics simulations, to identify novel c-MET inhibitors with unique structural frameworks. Among several promising candidates, compound 10 exhibited potent c-MET inhibition and selective antiproliferative effects against the HCC cell line Hep3B. Further molecular dynamics simulations confirmed the binding stability of compound 10 with c-MET, highlighting key interactions that contribute to its inhibitory activity. These findings provide valuable insights into the development of c-MET inhibitors with potential therapeutic applications for HCC.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1305-1312"},"PeriodicalIF":3.5,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of Potent FGFR2/3 Inhibitors to Overcome Mutation Resistance and Treat Achondroplasia. 发现有效的FGFR2/3抑制剂克服突变抵抗和治疗软骨发育不全。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-26 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00294

Donglin Fu, Tian Han, Zimo Yang, Yuanfeng Xia, Zhilong Hu, Fanglong Yang, Siqi Wang, Lei Jin

引用次数: 0

Exploring Covalent Modulators in Drug Discovery and Chemical Biology. 探索共价调节剂在药物发现和化学生物学中的应用。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-26 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00335

Ashley Adams, Lori Ferrins

引用次数: 0

Development of a Highly Potent Neurokinin‑3 Receptor Inhibitor: Design, Synthesis, and Evaluation. 高效神经激肽- 3受体抑制剂的开发：设计、合成和评价。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-26 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00230

Shengmin Ji, Hui Wang, Hengwei Xu, Wenjing Zhang, Yifei Yang, Chunmei Li, Wenyan Wang, Liang Ye, Jianzhao Zhang, Hongbo Wang, Jingwei Tian, Fangxia Zou

{"title":"Development of a Highly Potent Neurokinin‑3 Receptor Inhibitor: Design, Synthesis, and Evaluation.","authors":"Shengmin Ji, Hui Wang, Hengwei Xu, Wenjing Zhang, Yifei Yang, Chunmei Li, Wenyan Wang, Liang Ye, Jianzhao Zhang, Hongbo Wang, Jingwei Tian, Fangxia Zou","doi":"10.1021/acsmedchemlett.5c00230","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00230","url":null,"abstract":"The neurokinin-3 receptor (NK3R) has emerged as a promising therapeutic target. Recent evidence indicates that oral administration of an NK3R antagonist to block neurokinin B signaling significantly alleviates hot flash symptoms. Despite this potential, only one NK3R ligand (ESN-364) has been clinically approved to date. To address this gap, we developed a series of imidazole-piperazine derivatives (13a-13l, 17a-17f, and 22a-22i) through rational design and synthesis. Molecular docking validated the structural rationale, with compound 22i demonstrating superior target binding potency and robust NK3R inhibitory activity. Notably, 22i exhibited an enhanced membrane permeability and high oral bioavailability. In vivo efficacy studies revealed that oral 22i effectively suppressed luteinizing hormone levels, supporting its potential for further optimization.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1373-1382"},"PeriodicalIF":3.5,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0